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CELL II > Lipid Synthesis + Degradation > Flashcards

Lipid Synthesis + Degradation Flashcards

1
Q

How are fats obtained?

A

from diet or made new from carbohydrates

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2
Q

Role of fats in biological functions?

A

Membranes
Uptake of lipid soluble vitamins
As precursors of steroid hormones
Energy store

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3
Q

Why is fat a vital store of energy?

A 
The energy content of fat per gram is over twice that 
of either carbohydrate or protein 
1g fat  - 37kj
1g protein - 17kj
1g carbohydrate - 16kj
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4
Q

Health implications of fat?

A
  • 40% of energy of British Diet from fat
  • Adult obesity rose from 14.9% to 25.6% between 1993 and 2014
  • Obesity BMI 30kg/m^2
  • 30,000 premature deaths annually
  • £4.2bn in 2007 + increased to 6.3bn in 2015
  • 75% of will be obese within 15 years
  • Government policy is to reduce this to <35%
  • In 2016 :
    62. 8% of adults overweight/obese
    30. 3% of children overweight/obese
    26. 1% of adults + 16% of children obese
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5
Q

What molecules affect lipid metabolism?

A

FA
Triglycerides or Neutral Fats
Cholesterol

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6
Q

How body uses fat?

A
  • Calorific intake > consumption then excess –> fat
  • Cardiac muscle use fats as preferred energy source
  • Dietary carb most common source of metabolic building blocks although some AA can also be used
  • Fats stored in adipose tissue but majority synthesised in liver
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7
Q

Structure of FA?

A
  • Chains of methyl groups
  • Terminal carboxyl group
  • Double bonds in cis conformation
  • Humans unable to create double bonds less than position 9
  • Essential FA obtained from diet
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8
Q

Where does lipid synthesis occur?

A

cytosol of liver hepatocytes

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9
Q

Where does lipid degradation occur?

A

via beta oxidation in mitochondria of liver hepatocyte

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10
Q

Features of triglycerides?

A

-Neutral fats (how most fats are stored)
-3FA attached to a glycerol backbone
-glycerol made from glycolysis by glycerol-3-
phosphate
-glycerol fed into glycolysis

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11
Q

What does FA synthesis require?

A

ACoA
NADPH
ATP
-It involves sequential addition of 2 two C units derived from ACoA

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12
Q

What does transfer of ACoA to cytosol provide?

A

40% NADPH (60% additional NADPH from pentose phosphate pathway)

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13
Q

How liver makes FA?

A

-Cell wants to generate ATP
-ACoA feed into Krebs cycle
-ACoA + oxaloacetate
-forms citrate –> ETC
BUT in hepatocyte make FA for energy
-citrate transported out of mitochondria + remove ACoA
-ACoA makes FA +/ cholesterol

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14
Q

Fate of FA after made in liver?

A

-Remain in liver (liver lipids)
-Transported to peripheral tissue adipocytes for storage via:
exported bound within lipoproteins
bound to albumin as free FA

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15
Q

Describe transfer of ACoA to cytosol

A

-formation of citrate in mitochondria
-pumped into cytosol via citrate-malate antiport
-cyclical process as if mitochondria’s citrate removed then removing component of Krebs cycle (as we are
removing oxaloacetate as it is a cycle)
-citrate breaks down -> ACoA + oxaloacetate
-oxaloacetate -> malate
-malate -> pyruvate + NADH
-pyruvate transported into mitochondrion
-pyruvate -> oxaloacetate

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16
Q

What drives rate-limiting 1st step of FA synthesis?

A

Vital irreversible regulatory step + driven (activated)
in part by amount of citrate present (positive feed forward) as amount of citrate in a cell will rise when flow of glucose via glycolytic pathway increased

Note that the ACoA binds to a molecule that allows the reaction to occur, this
molecule is acyl carrier protein (ACP).
The reaction requires the vitamin biotin to work. The reaction requires ATP

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17
Q

What drives rate-limiting 1st step of FA synthesis?

A

Vital irreversible regulatory step + driven (activated)
in part by amount of citrate present (positive feed forward) as amount of citrate in a cell will rise when flow of glucose via glycolytic pathway increased

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18
Q

What inhibits rate-limiting 1st step of FA synthesis?

A

end product palmitate (negative feedback)

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19
Q

What inhibits rate-limiting 1st step of FA synthesis?

A

end product palmitic acid (negative feedback)

20
Q

Equation for rate-limiting 1st step of FA synthesis?

A

ACoA (C3) + ATP + HCO3- -> malonylCoA (C2) + ADP + Pi

via Acetyl-CoA carboxylase

21
Q

Equation for rate-limiting 1st step of FA synthesis?

A

ACoA (C2) + ATP + HCO3- -> malonylCoA (C3) + ADP + Pi

via Acetyl-CoA carboxylase

22
Q

What’s expression of Acetyl-CoA carboxylase controlled by?

A

Increased by high carbohydrate + low fat

Decreased by low carbohydrate + high fat

23
Q

Describe FA elongation

A

-rate-limiting step
-malonyl CoA + ACP
-forms malonyl-ACP (C3)
-2nd ACoA binds to ACP
-undergoes a condensation reaction with malonyl-ACP
-forms CO2 + Aceto-acetyl-ACP (C4)
-3 reactions : reduction, dehydration, another reduction coming out as butyryl-ACP (C4)
-butyryl ACP + malonyl-ACP - condensation
-forms 2nd CO2 , now
we have a 6-carbon molecule.
So this reaction allows addition of 2
carbon units each time in the form of
ACoA. The two reduction reactions
require NADPH, which we have
generated through the citrate-malate
transporting or the pentose-
phosphate pathway.
All the enzymes required for the
reactions above form a multi-functional
complex called Fatty acid synthase,
which exists as a dimer. By having a
multi-enzyme complex all the reactions
to occur are very close to each other
and the products of one reaction are
very close to the active site of the next
enzyme in the chain.

As the fatty acid chain is increased as the enzyme goes around and around in the
cycle (adding the carbons and doing the reductions and dehydrations etc.) above
until the chain reaches the required length and is released.

24
Q

Describe FA elongation

A
  • rate-limiting step
  • malonylCoA + ACP -> malonyl-ACP (C3)
  • 2nd ACoA + ACP -> acteyl-ACP (C2)
  • acteyl-ACP + malonyl-ACP - condensation
  • forms CO2 + aceto-acetyl-ACP (C4)
  • 3 reactions : reduction, dehydration, another reduction coming out as butyryl-ACP (C4)
  • butyryl ACP + malonyl-ACP - condensation
  • forms 2nd CO2 + C6
  • allows addition of 2 C units each time - ACoA
  • 2 reductions require NADPH
  • enzymes required form a multi-functional complex called FA synthase (dimer)
  • multi-enzyme complex allows all reactions are close to each other + products of 1 reaction are close to active site of next enzyme in chain
25
Q

Role of FA synthase?

A

multi-enzyme complex allows all reactions are close to each other + products of 1 reaction are close to active site of next enzyme in chain, FA chain increased as enzyme goes around + around in cycle (adding C, doing reductions + dehydrations) until chain reaches required length + released

26
Q

Feature of intermediates in FA elongation?

A

covalently linked to acyl carrier protein (ACP)

27
Q

Features of cholesterol?

A
  • Rigid hydrophobic molecule insoluble
  • Precursor of sterols, steroids, bile salts
  • Transported in circulation as cholesteryl esters
  • Cannot be oxidised to O2 + H2O so provide no energy
  • Vital membrane components
  • Cholesterol imbalance –> sig health issues
28
Q

Describe cholesterol synthesis

A

-synthesised mostly in the ER
-over 30 steps involved
-activation of acetate -> acetyl-CoA
-major regulatory step:
3-hydroxyl-3-methylglutaryl CoA (HMGCoA) -> mevalonate
-cholesterol inhibits HMGCoA reductase (enzyme involved in its own synthesis)
-difficult to reduce circulating cholesterol by diet alone as endogenous synthesis is increased

29
Q

Steps of FA degradation?

A

1 - Mobilising FA in adipocyte
2 -Transported back to liver + activation in hepatocyte cytosol
3 - Degradation in hepatocyte mitochondria via β-oxidation

30
Q

Describe mobilisation of FA?

A
  • mobilsation of FA via stimulation of 7TMD GPCR
  • generates cAMP
  • cAMP activates PKA
  • PKA phosphorylates triacylglycerol lipase (activates it)
  • triacylglycerol -> diacylglycerol via triacylglycerol lipase
  • diacylglycerol acted upon by lipases
  • free glycerol + free FA
31
Q

Role of triacylglycerol lipase?

A

triacylglycerol -> diacylglycerol

32
Q

Fate of glycerol?

A

-absorbed by liver
-converted back to glucose
-glycerol phosphorylated -> glycerol-3-phosphate
-glycerol 3-phosphate oxidized -> dihydroxyacetone phosphate
-isomerised to glyceraldehyde 3 phosphate
-glyceraldehyde 3-phosphate :
can go into glycolysis to produce ATP
most go into gluconeogenesis to synthesise glucose which will be released into circulation

33
Q

Describe activation of FA in hepatocyte cytosol

A
  • FA transported to liver + activated by acyl-CoA synthase in cytoplasm
  • acyl-CoA transported across inner mitochondrial membrane bound to alcohol carnitine
  • acyl-CoA + carnitine -> acyl carnitine
  • transported via translocase
  • acyl-carnitine -> carnitine + releases acyl with CoA
  • molecule get across membrane
34
Q

Effect of carnitine deficiency?

A

cause muscle weakness or even death

35
Q

Role of alcohol carnitine?

A

binds to acyl-CoA so it can be transported acros IMM

36
Q

What’s carnitine inhibited by?

A

malonyl-CoA (1st thing in FA synthesis) so if builds up, then synthesis so no degradation transport

37
Q

How’s FA oxidation reverse of synthesis?

A
  • Acyl-CoA degraded by generation of 2 C units (reformation of ACoA)
  • Series of oxidation, hydration, oxidation, thiolysis
  • Breakdown continues until chain length of FA reaches a certain length
38
Q

Products of FA oxidation?

A

FADH2
NADH
ACoA

39
Q

Describe β-oxidation

A

-β-oxidation generates ACoA, FADH2, NADH
-FADH2 + NADH form ATP
-ACoA enter citric acid only in presence of glycolysis to
produce ATP (which liver cells don’t tend to do, so this
doesn’t tend to occur)
-complete oxidation of palmitate yields 106 ATP
-cleaving off FA until it reaches certain chain length
-if odd chain length = proprionyl-CoA in last round of oxidation
-odd numbered double bonds removed by isomerase
-even double bonds removed by reductase + isomerase
-BUT ACoA tends to be converted to ketone bodies

40
Q

Role of isomerase?

A

removes odd numbered double bonds

removes even numbered double bonds with reductase

41
Q

Role of reductase?

A

removes even numbered double bonds with isomerase

42
Q

Describe ketogenesis

A

-ACoA -> acetoacetyl-CoA
-acetoacetyl-CoA -> HMG-CoA (β-hydroxy β-methylglutaryl-CoA)
-HMG-CoA -> acetoacetate
-acetoacetate reduced :
to 3-β-hydroxybuterate
or non-enzymatically to acetone

43
Q

What’s ketogenesis regulated by?

A

Insulin/glucagon ratio

High when low ratio as this inhibits ACoA carboxylase (rate limiting step in FA synthesis)

44
Q

Fate of ketone bodies?

A

-Energy source for cardiac muscle + renal cortex
(dependent on flow of carbohydrate in glycolysis)
-Starvation up to 75% of brains energy derived from acetoacetate

45
Q

Summary of lipid breakdown?

A
  • TG -> glycerol + FA in adipocytes
  • Glycerol fed in to glycolysis or gluconeogenesis
  • In liver FA activated + transported to mitochondria
  • FA are broken down in a step by step manner -> ACoA
46
Q

Hormone regulation of fat metabolism?

A 
INSULIN :
↑ glycolysis  in the liver
↑ FA synthesis in the liver
↑ TG in adipose tissue
↓ β-oxidation
GLUCAGON + A :
↑ TG mobilisation
47
Q

Summary of FA synthesis + degradation?

A 
SYNTHESIS :
Cytosol
Intermediates linked to acyl-carrier protein
Sequential addition 2C
Reductant NADPH
FA synthase enzyme complex

Reciprocally regulated

DEGRADATION :
Mitochondria
Intermediates linked to coenzyme-A
Sequential removal 2C
Oxidants FAD and NAD
Carried out be individual enzymes

CELL II (9 decks)

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